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WO2003013501A1 - Composition pharmaceutique amelioree contenant un agent recepteur alpha active de proliferation des peroxisomes (ppar alpha) et procede de preparation de cette composition - Google Patents

Composition pharmaceutique amelioree contenant un agent recepteur alpha active de proliferation des peroxisomes (ppar alpha) et procede de preparation de cette composition Download PDF

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Publication number
WO2003013501A1
WO2003013501A1 PCT/BE2002/000051 BE0200051W WO03013501A1 WO 2003013501 A1 WO2003013501 A1 WO 2003013501A1 BE 0200051 W BE0200051 W BE 0200051W WO 03013501 A1 WO03013501 A1 WO 03013501A1
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WO
WIPO (PCT)
Prior art keywords
composition
agent
fenofibrate
ppar
disintegrating agent
Prior art date
Application number
PCT/BE2002/000051
Other languages
English (en)
Inventor
Francis Vanderbist
Philippe Baudier
Antonio Sereno
Original Assignee
Laboratoires Smb Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoires Smb Sa filed Critical Laboratoires Smb Sa
Priority to DE60210626T priority Critical patent/DE60210626T2/de
Priority to AT02748487T priority patent/ATE322896T1/de
Priority to PCT/BE2002/000123 priority patent/WO2003013500A1/fr
Priority to EP02748487A priority patent/EP1414433B1/fr
Priority to CA002456713A priority patent/CA2456713A1/fr
Publication of WO2003013501A1 publication Critical patent/WO2003013501A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • An oral semi-solid composition containing at least one peroxisome proliferator activated alpha agent (PPAR ⁇ ) at a therapeutical dose, a polyglycolized glyceride and an hydrophilic disintegrating agent.
  • PPAR ⁇ peroxisome proliferator activated alpha agent
  • Fibrates are old hypolipidemic drugs with pleitropic effects on lipid metabolism. Their intimate molecular mechanisms of action have been mysterious for a long time. Recently, it has been shown that the pharmacological effect of fibrates depends on their binding to "Peroxisome Proliferator Activated Receptor alpha" (PPAR alpha). The binding of fibrates to PPAR induces the activation of the inhibition of multiple genes involved in lipid metabolism through the binding of the activated PPAR alpha to "Peroxisome Proliferator Response Element” (PPRE) located in the gene promoters. Furthermore, it was recently demonstrated that fibrates are potent antiinflammatory molecules through an indirect modulation of the nuclear-factor-Kappa B activity.
  • PPAR alpha Peroxisome Proliferator Activated Receptor alpha
  • Fenofibrate or P-(4-chlorobenzoyl)-phenoxy isobutyrate isopropyl ester is useful for the treatment of adult patients with very high elevations of serum triglyceride levels and/or cholesterol levels.
  • the usual daily dosage was 300 mg which was administered in two or three doses.
  • a suprabioavailable composition of fenofibrate was developed and marketed by Laboratoires Foumier, France (EP 0030532). 200 mg of fenofibrate from this composition was bioequivalent to 300 mg of the initial composition.
  • Fenofibrate is absorbed as fenofibric acid which is responsible for the pharmacological activity.
  • Fenofibric acid resulting from the hydrolysis of fenofibrate is extensively bound to plasma albumin.
  • the plasma half-life is about 20 hours.
  • Fenofibric acid is excreted predominantly in the urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid and its glucuronides.
  • Fenofibrate is presently available in a pharmaceutical dosage form consisting of hard gelatin capsules containing fenofibrate, lactose starch and magnesium stearate. After oral administration, during a meal, about 60% of the dose of this conventional form is effectively absorbed and found in the blood as fenofibric acid, the main metabolite responsible for pharmacological activity.
  • the first attempt to improve the bioavailability of fenofibrate was performed by Ben-Armor et al, by solubilizing the fenofibrate in dimethyl isosorbide, a nonaqueous solvent with a miscible wetting agent (Labrafil M1944CS) with HLB of between 3-4.
  • Labrafil M1944CS miscible wetting agent
  • colloidal silicon oxide was added to increase the viscosity.
  • the liquid so obtained was placed in hard gelatin capsules which, to be leak proof, were sealed. In vivo studies with this formulation indicate that there was no statistically significant difference in bioavailability between this liquid formulation and the conventional form when the product was given with food.
  • European Patent Application 0330532 discloses a fenofibrate composition wherein the fenofibrate powder is co-micronized with a solid wetting agent. Sodium lauryl sulfate is described as the solid wetting agent of choice. The co-micronized powder so obtained is mixed with capsule filling excipient such as lactose, starch, polyvinyl pyrollidone and magnesium stearate. A formulation of this composition is actually available on the French market under the trade name Lypanthyl ® 200, Fournier, France. A study comparing this formulation (Lypanthyl ® 200) to the conventional form was undertaken and a statistically significant increase in bioavailability was indicated for the former. In particular, it was found that 67 mg of the new form gives the same amount absorbed as does 100 mg of the conventional form.
  • the Canadian patent 2,214,895 describes an improved formulation of fenofibrate obtained by making a solid dispersion of fenofibrate and a disintegrating agent.
  • the filling of hard gelatin capsules with a micronized powder is a difficult operation, particularly if weight variation homogeneity is considered.
  • This patent describes the use of: a) an inert hydrosoluble carrier covered with at least one layer containing fenofibrate active ingredient in a micronized form having a size smaller than 20 microns ( ⁇ m), a hydrophilic polymer and, optionally, a surfactant, said hydrophilic polymer making up at least 20% by weight of an (a) and : b) optionally one or several outer phase(s) or layer(s).
  • composition described in the US patent 6,277,405 allows indeed to improve the bioavailability of fenofibrate in comparison with the commercial forms available on the market for several years (TRICOR ® 200, LIPIDIL ® 200, LIPANTHYL ® 200, Fournier, France) and corresponding to the older US patent EP 0330532.
  • the advantages of the semi-solid formulations are multiple for a PPAR derivative: protection of the active ingredient from air and humidity, possibility of increasing the dissolution rate of the molecule and hence of bioavailability, diminution of the risk of contamination of the operator, diminution of the risk of cross contamination, no possibility of demixing under the effect of vibrational mixing during manufacturing process, facility of the production process.
  • the choice of the nature of the formulation of course influenced the stability of the pharmaceutical form and the bioavailability of the drug contained in it.
  • a maximum bioavailability is achieved by preparing and keeping the drug in the amorphous/solubilized state in a solid dispersion or in a lipid-based formulation.
  • the barrier we are avoiding is the compound « washing-out » of solution to a large extent into a insoluble crystalline form during the dissolution/release step in vivo.
  • the present invention provides a pharmaceutical formulation for treating hyperlipidemia and/or hypercholesterolemia in a mammal, which contains an effective amount of a PPAR ⁇ agent or a mixture of PPAR ⁇ agents, advantageously fenofibrate, an excipient which contains one or more polyglycolyzed glycerides, the polyglycolyzed glycerides preferably having an HLB value of at least about 10, and one disintegrating agent.
  • PPAR agents are agents having a "peroxisome proliferation activated receptor activating effect", i.e. agents activating the binding of PPAR to peroxisome proliferator response element (PPRE), as well as agents activating the PPAR for its binding to PPRE.
  • PPRE peroxisome proliferator response element
  • the agent as such, or a metabolite thereof , or a compound generated by the organism due to the presence of the agent is bound to the PPAR, whereby inducing the binding of PPAR to PPRE.
  • PPAR agents are agents for which the data determined by measuring the receptor-activating effect of a certain compound are statistically judged as being significantly different from the control data determined in the absence of the compound.
  • the PPAR agent is advantageously an agent with a low water solubility, such as a water solubility similar or smaller to the water solubility of fenofibrate (for example a water solubility expressed in g/l corresponding to less than 5 (preferably less than 2) times the solubility of fenofibrate in water (pH 7, temperature 20°C).
  • a water solubility similar or smaller to the water solubility of fenofibrate for example a water solubility expressed in g/l corresponding to less than 5 (preferably less than 2) times the solubility of fenofibrate in water (pH 7, temperature 20°C).
  • the PPAR agent is more precisely a PPAR ⁇ agent, such as a compound of the fibrate family, such as fenofibrate, ciprofibrate, Clofibrate, Gemfibrozil, Bezafibrate or combinations thereof, fenofibrate and combinations containing fenofibrate being most preferred.
  • a PPAR ⁇ agent such as a compound of the fibrate family, such as fenofibrate, ciprofibrate, Clofibrate, Gemfibrozil, Bezafibrate or combinations thereof, fenofibrate and combinations containing fenofibrate being most preferred.
  • the present invention is also particularly advantageous for the production of oral solid dosage forms which can be prepared by melting the excipients in which the fenofibrate is at least partially soluble, whereby particle size specifications are not required.
  • the present invention also relates to the addition of a suspension stabilizer to the molten solution of PPAR ⁇ (such as fenofibrate)- polyglycolyzed glycerides.
  • PPAR ⁇ such as fenofibrate
  • the suspension stabilizer avoids the formation of PPAR ⁇ crystals, such as fenofibrate crystals, during the cooling of the filled hard gelatin capsules.
  • Suitable suspension stabilizers which may be used are, for example, cellulose derivatives, such as hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethylcellulose, povidone, poloxamers, .alpha., .OMEGA.-hydroxy-poly(oxyethylene) poly(oxypropylene)-poly(oxyethylene)bloc polymers.
  • cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethylcellulose
  • povidone poloxamers
  • .alpha., .OMEGA hydroxy-poly(oxyethylene) poly(oxypropylene)-poly(oxyethylene)bloc polymers.
  • Other suspension stabilizers equivalent to these stabiliers may, of course, also be used.
  • the present invention is also particularly advantageous for the production of a pharmaceutical composition in that the hot, homogeneous PPAR ⁇ (such as fenofibrate) solution is filled in hard gelatin capsules. This filling process permits to ensure a very precise PPAR ⁇ (such as fenofibrate) amounts in each capsule.
  • the present invention is particularly advantageous as well for the production of the present pharmaceutical composition in that the process for manufacturing the composition requires very few steps such as melting, mixing and filling. This renders the present manufacturing process extremely cost effective when compared to one using co-micronization of powders.
  • Polyglycolyzed glycerides which may be used in the present invention are generally mixtures of known monoesters, diesters and triesters of glycerols and known monoesters and diesters of polyethylene glycols with a mean relative molecular mass between about 200 and 6000. They may be obtained by partial transesterification of triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids using known reactions.
  • the fatty acid component contains 8-22 carbon atoms, particularly 10-18 carbon atoms.
  • natural vegetable oils which may be used include palm kernel oil and palm oil. However, these are only examples.
  • the polyol suitably has a molecular weight in the range of about 200-6000 and preferably contains polyethylene glycol, although other polyols may be employed, such as polyglycerols or sorbitol. They are available on the market under the trade name Gelucire ® (Gattefosse, France).
  • the HLB of the polyglycolized glycerides is preferably at least about 10, and more preferably between about 12 and 15.
  • the melting point of the polyglycolized glycerides may be between about 18. degree. C. and 60. degree. C.
  • two or more polyglycolized glycerides may be mixed in order to adjust both the HLB value and the melting point to a desired value.
  • the HLB value and melting point of the composition may further be adjusted with the addition of components such as polyethylene glycols, polyoxyethylene glycols fatty acid esters, and fatty acid alcohols.
  • components such as polyethylene glycols, polyoxyethylene glycols fatty acid esters, and fatty acid alcohols.
  • the present invention is not bind by any particular theories, one plausible mechanism of operation for the present invention is that upon cooling, the melted mixture of hot PPAR ⁇ (such as fenofibrate)- polyglycolized glycerides maintains the PPAR ⁇ (such as fenofibrate) in liquid form.
  • the gastrointestinal fluids are able to dissolve the PPAR ⁇ (such as fenofibrate) due to the HLB value of the excipient mixture, whereby PPAR ⁇ (such as fenofibrate) is readily absorbed.
  • the release of the drug from this kind of semi-solid lipophilic matrix is operated by a phenomenon of erosion-diffusion of the form when it is in contact with the gastro-intestinal fluids. As most excipients have relatively lipophilic properties, the release of the drug from the composition is relatively slow.
  • hydrophilic excipients disintegrating agents not soluble in the fatty mass.
  • hydrophilic excipients may be the following ones but are not restricted to them: sodium starch glycolate, sodium croscarmellose, crospovidone, pregelatinized starch, maize starch, Aerosil ® (colloidal silicone dioxide). These kinds of hydrophilic substances while not soluble are able to be dispersed homogeneously in the fatty mass and remain homogeneously dispersed after capsule filling and cooling.
  • the invention relates also to method for treating or preventing hyperlipidemia or hypercholesterolemia in a patient, in which at least an effective amount of a peroxisome proliferator activated receptor agent is orally administered to the patient simultaneously with at least one polyglycolized glyceride and one hydrophilic disintegrating agent.
  • the PPAR agent, the polyglycolized glyceride and the disintegrating agent are preferably of the type disclosed for the composition of the invention.
  • the invention further relates to a process for the preparation of an oral semi-solid or liquid composition containing at least an effective amount of PPAR agent, at least one polyglycolised glyceride and one hydrophilic disintegrating agent, in which the PPAR agent in powder form and hydrophilic disintegrating agent are mixed to a molten mixture containing at least one polyglycolised glyceride.
  • the PPAR agent and the hydrophilic disintegrating agent are mixed successively with the molten mixture.
  • the PPAR agent is first mixed with the molten mixture, and before adding the hydrophilic disintegrating agent, the homogeneous dispersion of the PPAR powder in the molten mixture is controlled
  • the weight ratio polyglycolized glyceride(s)/hydrophilic disintegrating agent in the composition of the invention or in the method of the invention or in the process of the invention is for example comprised between 100 and 0.1 , advantageously between 50 and 2, preferably between 40 and 4, for example between 8 and 25.
  • the weight ratio PPAR agent/hydrophilic disintegrating agent in the composition of the invention or in the method of the invention or in the process of the invention is for example comprised between 100 and 0.1 , advantageously between 50 and 2, preferably between 40 and 4, for example between 6 and 25.
  • the weight ratio PPAR agent/polyglycolized glyceride(s) in the composition of the invention and in the method of the invention or in the process of the invention is for example comprised between 10 and 0.1 , advantageously between 5 and 0.5, preferably greater than 1 , such as between 1.1 and 2, for example 1.2, 1.5, etc.
  • Figure 1 is a graph showing the in vitro comparative dissolution profiles of 2 semi-solid formulations of fenofibrate with and without disintegrant
  • Figure 2 is a graph showing the in vitro comparative dissolution profiles of 2 semi-solid fenofibrate compositions containing different disintegrating agents
  • Figure 3 is a graph showing the pharmacokinetic results of comparative study in 18 volunteers for fenofibrate (log-transformed data).
  • fenofibrate is used as example of PPAR ⁇ agent.
  • fenofibrate is homogeneously dispersed in the mass add the hydropropylcellulose at 75°C and under mixing. Finally add the disintegrating agent at 75°C and under mixing.
  • the disintegrating agent is not dissolved in the fatty excipients but is homogeneously dispersed in the mass. Start the filling of hard gelatine or hypromellose capsules (at 70°C). Allow the capsules to cool until 30°C. At this temperature, the product becomes solid. Package adequately the capsules.
  • compositions 1 to 5 are given hereinbelow:
  • composition 2 Fenofibrate 200
  • the dissolution medium was 900 ml of an acidic (pH 1.2) dissolution medium containing Polysorbate 80 (2 %) as surfactant and pepsin (3.2 g/l) as enzyme.
  • composition corresponding to the present invention allows to increase the bioavailability of fenofibrate in humans after an oral administration. Therefore, pharmacokinetic studies have been performed:
  • LIPIDIL-TER ® 160 mg tablet is a suprabioavailable formulation of fenofibrate wherein the higher bioavailability of the drug is obtained by co- micronizing the fenofibrate together with a surfactant.
  • LIPIDIL-TER ® 160 mg is already on the market in several countries.
  • This study was a single dose, two treatments, two periods, two sequences, randomised, cross-over and with at least 8 days wash-out between the two periods.
  • the subjects were healthy Caucasian volunteers of both sexes (non- pregnant, non-breast-feeding), aged 18 to 50 years, non smokers or smoking less than 10 cigarettes per day.
  • the drugs (one tablet or one capsule containing 160 mg of fenofibrate in one intake during the two periods) were taken with food (a standardized breakfast). Blood samples were collected according to the following sampling schedule : pre-dose and 1h, 2h, 3h, 4h, 5h, 6h, 7h, 9h, 12h, 24h, 36h, 48h, 60h and 72 hours post-dose.
  • the plasma concentrations of fenofibrate were quantified using a fully validated LC/MS/MS method.
  • the continuous variables (AUC ⁇ , AUC ⁇ , C max , t- ⁇ /2 and MRT) were evaluated according to an univariate ANOVA based on log-transformed data. For Tmax, the non parametric Kruskal-Wallis test was used. Bioequivalence was evaluated using the Shuirman two one-sided t-test (90% Cl). The Kinetica Program (Innaphase ® ) has been applied for this calculations.
  • Table 1 Pharmacokinetic results and statistical analysis of comparative study in 18 volunteers for fenofibrate (log-transformed data)
  • LIPIDIL-TER ® 160 mg and FENOGAL ® LIDOSE ® 160 mg are bioequivalent after a single oral dose administration of each product in fed conditions. Indeed, the pharmacokinetics parameters AUC (AUC ⁇ and AUC T ), C max , T max , t 1 2 and MRT were within the predetermined confidence interval. Consequently, the present invention allows to obtain a similar suprabioavailable product as LIPIDIL-TER ® 160 mg but with a very simplier and cheaper manufacturing process.
  • compositions similar to compositions 1 to 5 have been prepared by replacing the fenofibrate powder by the following PPAR agents :

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Abstract

L'invention se rapporte à une composition orale semi-solide ou liquide pour le traitement de l'hyperlipidémie ou l'hypercholestérolémie chez des sujets humains. Cette composition comporte au moins une quantité efficace d'un agent recepteur alpha activé de prolifération des péroxisomes (PPARα), un glycéride polyglycolisé et un agent de désintégration hydrophile.
PCT/BE2002/000051 2001-08-07 2002-04-05 Composition pharmaceutique amelioree contenant un agent recepteur alpha active de proliferation des peroxisomes (ppar alpha) et procede de preparation de cette composition WO2003013501A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE60210626T DE60210626T2 (de) 2001-08-07 2002-07-17 Verbesserte pharmazeutische zusammensetzung mit einem ppar-alpha-mittel und verfahren zu ihrer herstellung
AT02748487T ATE322896T1 (de) 2001-08-07 2002-07-17 Verbesserte pharmazeutische zusammensetzung mit einem ppar-alpha-mittel und verfahren zu ihrer herstellung
PCT/BE2002/000123 WO2003013500A1 (fr) 2001-08-07 2002-07-17 Composition pharmaceutique amelioree contenant un agent ppar alpha et son procede de preparation
EP02748487A EP1414433B1 (fr) 2001-08-07 2002-07-17 Composition pharmaceutique amelioree contenant un agent ppar alpha et son procede de preparation
CA002456713A CA2456713A1 (fr) 2001-08-07 2002-07-17 Composition pharmaceutique amelioree contenant un agent ppar alpha et son procede de preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BEPCT/BE01/00133 2001-08-07
BE0100133 2001-08-07

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WO2003013501A1 true WO2003013501A1 (fr) 2003-02-20

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PCT/BE2001/000147 WO2003013607A1 (fr) 2001-08-07 2001-09-07 Composition pharmaceutique orale contenant une combinaison de fenofibrate et d'un inhibiteur de hmg-coa reductase
PCT/BE2002/000051 WO2003013501A1 (fr) 2001-08-07 2002-04-05 Composition pharmaceutique amelioree contenant un agent recepteur alpha active de proliferation des peroxisomes (ppar alpha) et procede de preparation de cette composition

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PCT/BE2001/000147 WO2003013607A1 (fr) 2001-08-07 2001-09-07 Composition pharmaceutique orale contenant une combinaison de fenofibrate et d'un inhibiteur de hmg-coa reductase

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US (2) US20070092567A1 (fr)
AT (2) ATE322896T1 (fr)
DE (1) DE60238059D1 (fr)
DK (1) DK1414496T3 (fr)
ES (1) ES2352189T3 (fr)
PT (1) PT1414496E (fr)
WO (2) WO2003013607A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011642A1 (fr) * 2003-08-05 2005-02-10 Galephar M/F Composition pharmaceutique a unite simple comprenant un melange de fibranne et un agent reducteur d'homocysteine
WO2005013940A1 (fr) * 2003-08-06 2005-02-17 Galephar M/F Compositions pharmaceutiques stables a liberation controlee contenant du fenofibrate et de la pravastatine
WO2013114153A3 (fr) * 2011-12-14 2013-10-31 Lts Lohmann Therapie-Systeme Ag Formulations de capsule et de cachet ayant des vitesses de dissolution améliorées pour fénofibrate

Families Citing this family (2)

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ES2352189T3 (es) 2011-02-16
WO2003013607A1 (fr) 2003-02-20
DE60238059D1 (de) 2010-12-02
US20150037414A1 (en) 2015-02-05
PT1414496E (pt) 2012-04-20
DK1414496T3 (da) 2011-01-24
ATE485058T1 (de) 2010-11-15
ATE322896T1 (de) 2006-04-15

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